Targeting CDK12 disrupts estrogen-receptor chromatin recruitment and ER-MED1 transcription in advanced ER+ breast cancer.
Overview
- Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
- Department of Surgery, Beaumont Hospital, Dublin, Ireland
- Department of Pathology, Beaumont Hospital, Dublin, Ireland
- The School of Pharmacy and Biomolecular Sciences, The Royal College of Surgeons University of Medicine and Health Sciences, Dublin, Ireland
- Carrick Therapeutics Ltd, Blanchardstown Corporate Park, Dublin, Ireland
- Women’s Cancer Research Center, Magee-Womens Research Institute, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, United States
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, United States
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55901, United States
- Beaumont RCSI Cancer Centre, Beaumont Hospital, Dublin, Ireland
Abstract
Background: Cyclin-dependent kinase 12 (CDK12) regulates general gene transcription elongation and plays multiple roles in RNA splicing, DNA damage-response, cell cycle, and genomic stability. However, transcriptional partners that guide CDK12-specific gene programs have not been identified. Genomic alterations in CDK12 have been observed in multiple cancers, exhibiting both pro-tumorigenic and tumor-suppressive functions, suggesting a context-dependent mechanism of action.
Methods: CDK12 copy number alterations and gene expression levels were analyzed in matched primary and brain metastatic patient tumors. Clinical significance was assessed by immunohistochemistry in a large cohort of primary breast cancer patient tumors. RNA sequencing, ChIP sequencing, and molecular studies were conducted to explore CDK12’s mechanism of action, and pharmacological studies were performed both in vitro and in vivo using models of advanced (endocrine-resistant and metastatic) estrogen receptor positive (ER+) disease.
Results: CDK12 amplifications and gene overexpression were observed in brain metastatic tumors. In ER+ primary patient tumors, high CDK12 protein expression was significantly associated with poor overall survival, particularly within the ER+/
Conclusion: This work describes a novel mechanism for CDK12, suggesting a potential vulnerability in ER+ breast cancer. These findings provide a basis for further investigation into the role of CDK12 inhibition as a therapeutic approach, particularly in advanced disease settings.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
The paper links to its data, not to its authors' code: see the Data section.
Tracing map
A tracing map links a paper to the code its authors published: this paper has none, so it has no map.
Data
Datasets cited
- figshare:16685680, at figshare; found in “Data availability”
- figshare:30618569, at figshare; found in “Data availability”
- figshare:30618884, at figshare; found in “Data availability”
Other data links
- ncbi.nlm.nih.gov/
geo , NCBI; found in “Data availability”
Data availability
Breast cancer models. Processed RNA-seq and ChIP-seq data from studies in LY2 cells are available in figshare, at https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 25 authors, 13 MeSH terms, 8 funders, 55 references.
Cite
This paper
Ottaviani, D., Ola, M., Allotta, A., Maati Chaibi, Y., Hickey, S., Jagust, P., Cosgrove, N., Cocchiglia, S., Bane, F., Fallon, R., Daly, G., Hegarty, A., Hudson, L., Sheehan, K., Kalsi, S., Shovlin, S., Powell, A., Bahl, A., Ainscow, E., . . . Young, L. (2026). Targeting CDK12 disrupts estrogen-receptor chromatin recruitment and ER-MED1 transcription in advanced ER+ breast cancer. Journal of the National Cancer Institute, 118(3), 404-421. https://
BibTeX
@article{ottaviani2026ta
author = {Ottaviani, Daniela and Ola, Mihaela and Allotta, Alessandra and Maati Chaibi, Yasmine and Hickey, Seán and Jagust, Petra and Cosgrove, Nicola and Cocchiglia, Sinéad and Bane, Fiona and Fallon, Ramón and Daly, Gordon and Hegarty, Aisling and Hudson, Lance and Sheehan, Katherine and Kalsi, Shannon and Shovlin, Stephen and Powell, Aoibhín and Bahl, Ash and Ainscow, Ed and Oesterreich, Steffi and Lee, Adrian V and Couch, Fergus J and Hill, Arnold D K and Varešlija, Damir and Young, Leonie},
title = {{Targeting CDK12 disrupts estrogen-receptor chromatin recruitment and ER-MED1 transcription in advanced ER+ breast cancer}},
journal = {Journal of the National Cancer Institute},
year = {2026},
month = mar,
volume = {118},
number = {3},
pages = {404--421},
publisher = {Oxford University Press},
issn = {0027-8874},
doi = {10.1093/
url = {https://
pmid = {41092317},
pmcid = {PMC13016824}
}
RIS
TY - JOUR
AU - Ottaviani, Daniela
AU - Ola, Mihaela
AU - Allotta, Alessandra
AU - Maati Chaibi, Yasmine
AU - Hickey, Seán
AU - Jagust, Petra
AU - Cosgrove, Nicola
AU - Cocchiglia, Sinéad
AU - Bane, Fiona
AU - Fallon, Ramón
AU - Daly, Gordon
AU - Hegarty, Aisling
AU - Hudson, Lance
AU - Sheehan, Katherine
AU - Kalsi, Shannon
AU - Shovlin, Stephen
AU - Powell, Aoibhín
AU - Bahl, Ash
AU - Ainscow, Ed
AU - Oesterreich, Steffi
AU - Lee, Adrian V
AU - Couch, Fergus J
AU - Hill, Arnold D K
AU - Varešlija, Damir
AU - Young, Leonie
TI - Targeting CDK12 disrupts estrogen-receptor chromatin recruitment and ER-MED1 transcription in advanced ER+ breast cancer
T2 - Journal of the National Cancer Institute
J2 - J Natl Cancer Inst
PY - 2026
DA - 2026/
VL - 118
IS - 3
SP - 404
EP - 421
SN - 0027-8874
PB - Oxford University Press
DO - 10.1093/
UR - https://
LA - en
ER -
CSL-JSON
{
"id": "10.1093/
"type": "article-journal",
"title": "Targeting CDK12 disrupts estrogen-receptor chromatin recruitment and ER-MED1 transcription in advanced ER+ breast cancer",
"container-title": "Journal of the National Cancer Institute",
"author": [
{
"family": "Ottaviani",
"given": "Daniela"
},
{
"family": "Ola",
"given": "Mihaela"
},
{
"family": "Allotta",
"given": "Alessandra"
},
{
"family": "Maati Chaibi",
"given": "Yasmine"
},
{
"family": "Hickey",
"given": "Seán"
},
{
"family": "Jagust",
"given": "Petra"
},
{
"family": "Cosgrove",
"given": "Nicola"
},
{
"family": "Cocchiglia",
"given": "Sinéad"
},
{
"family": "Bane",
"given": "Fiona"
},
{
"family": "Fallon",
"given": "Ramón"
},
{
"family": "Daly",
"given": "Gordon"
},
{
"family": "Hegarty",
"given": "Aisling"
},
{
"family": "Hudson",
"given": "Lance"
},
{
"family": "Sheehan",
"given": "Katherine"
},
{
"family": "Kalsi",
"given": "Shannon"
},
{
"family": "Shovlin",
"given": "Stephen"
},
{
"family": "Powell",
"given": "Aoibhín"
},
{
"family": "Bahl",
"given": "Ash"
},
{
"family": "Ainscow",
"given": "Ed"
},
{
"family": "Oesterreich",
"given": "Steffi"
},
{
"family": "Lee",
"given": "Adrian V"
},
{
"family": "Couch",
"given": "Fergus J"
},
{
"family": "Hill",
"given": "Arnold D K"
},
{
"family": "Varešlija",
"given": "Damir"
},
{
"family": "Young",
"given": "Leonie"
}
],
"container-title-short":
"volume": "118",
"issue": "3",
"page": "404-421",
"DOI": "10.1093/
"PMID": "41092317",
"PMCID": "PMC13016824",
"ISSN": "0027-8874",
"publisher": "Oxford University Press",
"URL": "https://
"language": "en",
"issued": {
"date-parts": [
[
2026,
3,
1
]
]
}
}
Similar papers
The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.
- [1] doi:10.1158/0008-5472.can-25-4018 [code]
- MIF-Induced CD74+ Microglia and Macrophages Promote Progression of Brain Metastasis and Are Clinically Relevant across Central Nervous System Disorders.Journal: Cancer researchIn common: other condition, mouse, cellular / molecular, 1 reference, 3 authors
- [2] doi:10.1038/s42003-026-10252-6 [code]
- RET signaling as a mediator of estrogen receptor positive breast cancer brain metastasis.Journal: Communications biologyIn common: other condition, mouse, cellular / molecular, 2 references, 2 authors
- [3] doi:10.1021/acs.jmedchem.6c00035
- The Discovery of TNG456: A Highly Potent, Selective, Brain-Penetrant MTA-Cooperative PRMT5 Inhibitor for the Treatment of &
lt;i& gt;MTAP& lt;/ i& gt;-Deleted Cancers. Journal: Journal of medicinal chemistryIn common: other condition, mouse, cellular / molecular, 2 references - [4] doi:10.1007/s00018-026-06139-8
- Cdk7 promotes neuritogenesis in cortical neurons and contributes to social behavior in mice.Journal: Cellular and molecular life sciences : CMLSIn common: mouse, cellular / molecular, 2 references
- [5] doi:10.3390/cancers18132092
- TGFB2 as a Prognostic Biomarker Associated with Myeloid-Enriched, Multi-Checkpoint-Activat
ed Immunosuppression in Diffuse Glioma: A Multi-Cohort Transcriptomic Study. Journal: CancersIn common: other condition, 2 references - [6] doi:10.1016/j.omton.2026.201215
- Reprogramming the immune suppressive tumor microenvironment in glioma enhances the efficacy of immune-mediated gene therapy.Journal: Molecular therapy. OncologyIn common: other condition, 2 references
- [7] doi:10.1016/j.xcrm.2026.102850 [code]
- Patient-derived organoids predict personalized drug response and reveal alternative therapeutic options in glioblastoma.Journal: Cell reports. MedicineIn common: other condition, mouse, 1 reference
- [8] doi:10.1371/journal.ppat.1014603
- Analysis of host and viral nascent and steady-state RNA levels in a human neuronal model of herpes simplex virus 1 infection.Journal: PLoS pathogensIn common: other condition, cellular / molecular, 1 reference
- [9] doi:10.3389/fphys.2026.1844142
- CRISPR/
Cas9-mediated & lt;i& gt;PHOX2B& lt;/ i& gt; functional knock-out in IMR32 neuroblastoma cells impairs neuronal excitability through dysregulation of ion channels genes. Journal: Frontiers in physiologyIn common: other condition, cellular / molecular, 1 reference - [10] doi:10.1186/s13059-026-04177-w [code]
- Genomic sequence evolution underlying human neocortical interareal diversification.Journal: Genome biologyIn common: mouse, cellular / molecular, 1 reference
Contribute
The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.
Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.
Claim this paper
Correct its record
Say what each link of this record is, remove the ones that are not the paper's, add the ones that are missing. The correction becomes a new version of the record, in its Versions section.
Request its removal
To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).
Discussion, reproductions, activity
Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.
Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.
Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.